Late diagnosis of chronic granulomatous disease.

Modern era advancements in medical care, with improved treatment of infections, can result in delayed diagnosis of congenital immunodeficiencies. In this study we present a retrospective cohort of 16 patients diagnosed with Chronic Granulomatous Disease (CGD) at adulthood. Some of the patients had a milder clinical phenotype, but others had a classic phenotype with severe infectious and inflammatory complications reflecting a profoundly impaired neutrophil function. It is therefore of great importance to investigate the individual journey of each patient through different misdiagnoses and the threads which led to the correct diagnosis. Currently the recommended definitive treatment for CGD is hematopoietic stem cell transplantation (HSCT). Although survival of our patients to adulthood might argue against the need for early HSCT during infancy, we claim that the opposite is correct, as most of them grew to be severely ill and diagnosed at a stage when HSCT is debatable with potentially an unfavorable outcome. This cohort stresses the need to increase awareness of this severe congenital immunodeficiency among clinicians of different specialties who might be treating undiagnosed adult patients with CGD.

Chronic granulomatous disease of childhood: an unusual cause of recurrent uncommon infections in a 61-year-old man.

Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency that affects 1 : 250,000 of the population, which is characterized by recurrent bacterial and fungal infections and by granuloma formation. We investigated a 61-year-old man presented with a 20-year history of a relapsing skin rash appearing as mildly pruritic and erythematous plaques affecting various body regions. Cutaneous biopsies were taken and sent for histology and tissue culture. Leucocyte function was assessed by determining the generation of reactive oxygen species. Bactericidal activity was assessed in the presence of autologous and homologous sera. Western blotting was performed for protein analysis of the reduced nicotinamide adenine dinucleotide phosphate oxidase system, and mutation screening was carried out using PCR amplification and sequence analysis. Examination of biopsies obtained from lesional skin indicated a suppurative granulomatous process. Tissue cultures grew Aspergillus nidulans and Aspergillus fumigatus (confirmed by PCR). A. nidulans has often been associated with CGD, and the leucocyte function tests supported this diagnosis. Direct DNA sequencing led to the identification of a hemizygous missense novel mutation in CYBB (c.907C>T), which predicts a p.His303Tyr amino-acid substitution in gp91-phox, thus confirming the diagnosis of CGD. In conclusion, we report a case of a rare inherited immunodeficiency, CGD, in a 61-year-old man, and describe the novel hemizygous missense mutation underlying the condition. Mild forms of usually fatal immunodeficiencies should be considered when assessing the occurrence of unusual infectious diseases in apparently healthy people.

A combined dietary-physical activity intervention affects bone strength in obese children and adolescents.

Obesity has become the most common pediatric chronic disease in the modern era. Recent data suggests that unlike obese adults, obese children and adolescents may have decreased bone strength. It was the objective to prospectively examine the short term effects of a 3 month combined dietary-physical activity intervention on anthropometric measures, body composition, fitness and bone strength in obese children. Twelve obese subjects completed the 3 m intervention and were compared to 12 obese age and gender matched controls. Bone strength was measured using quantitative ultrasound measurements of bone speed of sound (SOS). There were significant differences in changes of body weight (0.01 +/- 0.7 vs. 2.3 +/- 0.6 kg, p = 0.033), BMI percentiles (- 2.8 +/- 1.1 vs. - 0.2 +/- 0.2 %, p = 0.037), body fat percent (by skinfolds, - 1.5 +/- 0.8 vs. 0.7 +/- 0.5 %, p = 0.035), and endurance time (170 +/- 42 vs. 50 +/- 27 s, p = 0.045) in the intervention vs. control subjects, respectively. In addition, we found a significant difference in the change of bone SOS between the intervention and control group subjects (21.5 +/- 21.6 vs. - 87.0 +/- 37 m/s, p = 0.023). During the critical period of bone development of childhood and adolescence, a combined dietary-physical activity intervention leads to increased bone strength in obese children. These results highlight the importance of multi-disciplinary programs for the treatment of childhood obesity and its complications.

Human mast cells release Interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells.

BACKGROUND: Mast cells have recently been shown to control neutrophil recruitment during T-cell mediated cutaneous DTH reaction in vivo through TNF-alpha and MIP-2, the functional murine analogue of human IL-8. Although the nature of signals transmitted from T cells which activate mast cells has not yet been defined, we hypothesized that a direct cross-talk (i.e. heterotypic adhesion) between these two cell populations exists, as has previously been reported. AIMS: The present study was aimed at gaining insight into the functional role of mast cell-T cell contact in expression and release of IL-8, and its effect on neutrophil chemotaxis. METHODS: The IL-8 gene expression was identified by Affymetrix GeneChip arrays, validated by RT-PCR and the protein measured by ELISA. Chemotaxis was evaluated by using a modified Boyden chamber assay. RESULTS: Mast cells were found to express and release significantly higher concentrations of IL-8 on incubation with membranes obtained from activated, as compared to resting T cells. Supernatants obtained from these activated mast cells induced significant neutrophil chemotaxis that was inhibited by neutralizing mAb to IL-8. CONCLUSIONS: Thus, activated T cells, on heterotypic adhesion to mast cells, deliver the necessary signals for the latter to release cytokines and chemokines necessary for cell migration to sites of antigen challenge, thereby facilitating T-cell mediated inflammatory processes.

Unintentional childhood poisoning in the Sharon area in Israel: a prospective 5-year study.

OBJECTIVES: To study the epidemiology and risk factors for unintentional exposure to poisoning among the Jewish and the Arab population in the Sharon area in Israel. METHODS: We prospectively evaluated visits to the pediatric emergency department because of unintentional poisoning exposure, at the Meir General Hospital. We collected demographic data, substance exposure data, and the clinical outcome of the poisoning. RESULTS: During the 5 years of the study, 502 children were evaluated for unintentional poisoning, 84% Jewish and 16% Arabs; 88.5% occurred in children younger than 5 years, with a peak incidence at the age of 2 years (39.5%). Medications including hormones, vitamins, and antibiotics were the most common cause of exposure. Most children (95%) had no symptoms or abnormal findings on physical examination (84%), and most (85%) were discharged after several hours of observation. However, children of Arab origin presented with severe clinical manifestations because of a high rate of pesticide poisoning. There was 1 death from organic phosphate poisoning. CONCLUSION: Exposure to poisoning is commonly encountered in children. Pesticides exposure is more common in the Arab community and is usually associated with more severe clinical manifestations. Educational preventive programs are mandatory.

"Unresolving pneumonia" as the main manifestation of atypical Kawasaki disease.

Two cases of atypical Kawasaki disease (KD) manifested as persistent lobar lung consolidation, prolonged fever, and active inflammatory laboratory markers unresponsive to antibiotic treatment are reported. One of the children developed a giant coronary aneurysm. Atypical KD should be considered in the differential diagnosis of young children with prolonged fever and lobar consolidation unresponsive to antibiotics.

Convulsions and retinal haemorrhage: should we look further?

BACKGROUND AND AIMS: The prevalence of retinal haemorrhages after convulsions is not well established. As these haemorrhages are considered characteristic of child abuse, we investigated their occurrence after convulsive episodes to see whether the finding of haemorrhage should prompt further investigation. METHODS: Prospective study of 153 children (aged 2 months to 2 years), seen in the emergency department after a convulsive episode. After a thorough history and physical examination, a retinal examination was performed by an ophthalmologist. If findings were positive, further investigation was undertaken to rule out systemic disorder or child abuse. RESULTS: One child was found with unilateral retinal haemorrhages following an episode of a simple febrile convulsion. A thorough investigation uncovered no other reason for this finding. CONCLUSION: Retinal haemorrhages following a convulsive episode are rare. Such a finding should trigger an extensive search for other reasons, including child abuse.

Eosinophilic cystitis in a 4-year-old boy: successful long-term treatment with cyclosporin A.

A 4-year-old Jewish boy presented with dysuria, urinary dribbling, increased urinary frequency, and new onset of diurnal enuresis. An infiltrating solid mass involving the entire bladder wall was found. Biopsy revealed "tumor-forming" eosinophilic cystitis, a rare bladder lesion of unclear cause. Antitoxocariasis treatment was unsuccessful. High-dose corticosteroids failed. The child's clinical condition and bladder sonographic findings continued to deteriorate. Treatment with cyclosporin A was given for 8 months, with a complete clinical, radiologic, and histopathologic cure and no side effects. Two years of follow-up showed a complete recovery.

Early immunological defects in comatose patients after acute brain injury.

OBJECT: The aim of this prospective study was to evaluate the phagocytic, humoral, and cellular arms of the immune system in comatose patients shortly after severe brain injury and to compare the findings with those reported earlier in patients in a persistent vegetative state. The study was conducted in intensive care units and immunology laboratories of university-affiliated hospitals in central Israel. METHODS: The study group consisted of 14 men aged 16 to 65 years who were comatose as a result of acute brain injury due to mechanical trauma. All were studied within 72 hours of injury. Brain damage was severe in all cases (Glasgow Coma Scale score < 8). Healthy age- and sex-matched volunteers served as simultaneous controls. Infections arose in nine (75%) of the 12 patients in whom data were available; the cumulative mortality rate was 38% (five of 13 patients in whom outcome data were available). Every patient exhibited one or more defects in at least one arm of the immune system. Significant deficiencies were noted in neutrophil superoxide release, immunoglobulin (Ig)G, IgG1, IgM, C1q, C2, properdin, alternate C pathway, T cells, T helper cells, T suppressor cells, and natural killer cells. In an earlier series of patients examined by the authors months after the primary insult, these impairments were absent in most of the patients in the vegetative state. CONCLUSIONS: Significant deficiencies of the immune system, particularly the cellular arm, are precipitated by severe brain injury within 72 hours of the event. These impairments probably play a role in the high rate of complicating infections and multiple organ failure. Together with earlier findings, the results of this study indicate that if brain-injured patients survive these hazards, their immune system will eventually recover.

Diffuse muscular haemorrhage as presenting sign of juvenile systemic lupus erythematosus and lupus anticoagulant hypoprothrombinaemia syndrome.

Lupus anticoagulants are closely related to systemic lupus erythemathosus (SLE) and to thrombotic events. We describe a 12 year-old girl with a bilateral intramuscular haemorrhage of the gastrocnemius muscles as her main initial presentation of juvenile SLE. Laboratory work-up revealed lupus anticoagulant-hypoprothrombinaemia syndrome (LAHS) with very low levels of factor II due to autoantibodies. She showed a good initial clinical and laboratory response to prednisone therapy, however steroid dependency developed. To the best of our knowledge, this is the first case reported of juvenile SLE presenting with LAHS.

Quantitative ultrasound measurements of bone strength in obese children and adolescents.

Very few studies have examined the effect of childhood obesity on bone mineralization. The purpose of the present study was to determine bone strength by quantitative ultrasound (QUS) measurements of bone speed of sound (SOS) in obese children (n = 45; age range 6-17 yr). SOS was measured (by Sunlight Omnisense) in the mid-tibial and radial bones. Data were compared to age- and gender-matched norms of Israeli non-obese children. Radial and tibial SOS was significantly reduced in obese compared to non-obese children (p < 0.05). Bone SOS in obese children with BMI > 95th percentile was not significantly different from obese children with BMI from 85-95th percentile. Tibial and radial SOS were correlated with pubertal stage (r = 0.52, p < 0.005; and r = 0.35, p < 0.01, respectively), and with chronological age (r = 0.47, p < 0.005; and r = 0.32, p < 0.025, respectively). No significant correlation was found between endurance time as an indicator of fitness and bone SOS. Bone strength measured by QUS is reduced in obese children, but is not affected by the severity of obesity.

Quantitative ultrasound measurements of bone speed of sound in premature infants.

UNLABELLED: We measured bone speed of sound in premature infants by quantitative ultrasound. A total of 44 neonates participated in the study including 29 premature infants (median birth weight 1264 g, range 578-2420 g; median gestational age 31 weeks, range 24-36 weeks) and 15 full-term infants (median birth weight 3360 g, range 2700-3730 g; median gestational age 40 weeks, range 37-41 weeks). The left tibial speed of sound (SOS) was measured by quantitative ultrasound. Bone SOS was successfully measured in all infants. We found a significant correlation between tibial SOS and gestational age (r = 0.78, P < 0.0005), but a significant inverse correlation between tibial SOS and post-natal age (r = -0.78, P < 0.0005). Bone SOS was significantly (P < 0.05) higher in full-term infants (3101 m/s, range 2899-3314 m/s) compared to premature infants (2821 m/s, range 2516-3139 m/s), and compared to a subgroup of the premature infants who reached corrected age of full-term infants (2706 m/s, range 2516-2892 m/s, n = 13). Bone SOS was lower (2745 m/s, range 2533-3036 m/s, n = 16) in very low birth weight premature infants (birth weight < 1500 g). CONCLUSION: The results indicate that tibial speed of sound was reduced in premature infants (in particular very low birth weight) compared to full-term infants even when premature infants reached the corrected age of their full-term peers. The potential role of this technique in assessing osteopenia in premature infants warrants further exploration.

Ambulatory blood pressure monitoring in children with a solitary kidney - a comparison between unilateral renal agenesis and uninephrectomy.

BACKGROUND: In experimental animals, a reduction in renal mass leads to glomerulosclerosis of the residual parenchyma and eventual renal failure. In humans, however, data on the influence of nephrectomy or agenesis on future functional parameters and hypertension are as yet controversial. OBJECTIVE: To evaluate blood-pressure patterns in children with a solitary kidney as a result of either unilateral renal agenesis (URA) or uninephrectomy (UNX) and correlate them to the increase in size of the remaining kidney. METHODS: Twenty-eight children with a solitary kidney were divided into two groups: the URA group, with 18 subjects (13 male and five female, with a mean age of 9.6 +/- 3.9 years), and the UNX group, which contained 10 subjects (four male and six female, with a mean age of 14.0 +/- 2.7 years). The mean time since nephrectomy was 8.7 years. Each study group was assigned an age-, weight- and height-matched control group. In all subjects, ambulatory blood pressure monitoring was performed using the SpaceLabs model no. 90207. Daytime and night-time were defined as 0800-2200 h and 2200-0800 h, respectively. Urinalysis, serum creatinine and urea results were recorded for all the study group participants. The size of the remaining kidney was determined by ultrasound examination. The percentage increase in kidney size, as calculated from standard kidney-length-against-age nomograms was correlated to the percentage deviation from normal blood pressure values. RESULTS: The mean 24 h, daytime and night-time systolic blood pressure (SBP) readings were significantly higher in children in the URA group than in those in the corresponding control group (111.4 +/- 7.5 mmHg versus 106.9 +/- 6.7 mmHg, P < 0.004; 115.2 +/- 3.1 mmHg versus 110.7 +/- 3.4 mmHg, P < 0.004; and 105.2 +/- 2.6 mmHg versus 101.2 +/- 1.8 mmHg, P < 0.002, respectively). Daytime heart rate was found to be significantly reduced (84.4 +/- 5.2 versus 87.8 +/- 8.2 beats/min, P < 0.04). In the UNX group, 24 h mean, systolic and diastolic blood pressure (DBP), as well as heart rate, did not differ from control values. Daytime systolic and diastolic blood pressures were higher than those of the controls (119.8 +/- 4.0 mmHg versus 115.5 +/- 3.8 mmHg, P < 0.02; and 72.7 +/- 4.0 mmHg versus 70.0 +/- 11.0 mmHg, P < 0.02, respectively). Nocturnal dipping was present in all groups and was of equal magnitude in the corresponding control groups. The mean 24 h diastolic blood pressure load was significantly greater in URA patients than in controls (19.6 versus 10.8%, respectively, P < 0.01). In the UNX group, the blood pressure loads were similar to those of controls. The percentage increase in length of the remaining kidney was found to correlate positively with the percentage delta increase in both systolic and diastolic blood pressure. CONCLUSIONS: Compared with the age-, height- and weight-matched controls, the children with a solitary kidney caused by URA had an elevated mean 24 h SBP. In contrast, those with UNX had mean 24 h blood pressure values similar to those of their controls. A rise in SBP was, however, seen in both groups during the daytime hours. Thus, the presence of a solitary kidney, for whatever reason, may be pathogenetically linked to a raised blood pressure, and this linkage may be more pronounced in URA. The delta increase in size of the remaining kidney may serve as a prognostic indicator of blood pressure elevation.

In vitro effect of advanced glycation end-products on human polymorphonuclear superoxide production.

BACKGROUND: Advanced glycation end-products (AGEs) are elevated in the sera of diabetic patients. The latter are prone to severe bacterial infections. Advanced glycation end-products have been shown to modulate immune competent cell activities. In this study we examined the in vitro effect of advanced glycation end-products on superoxide anion generation by human polymorphonuclear leukocytes. MATERIALS AND METHODS: Advanced glycation end-products were prepared by incubation of bovine serum albumin (BSA) with glucose for 90 days. Superoxide production was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome c. The effect of advanced glycation end-products on superoxide production was evaluated in both baseline (nonstimulated) and stimulated (by either formyl-methionyl-leucyl-phenylalanine, or phorbol-myristate-acetate) polymorphonuclear leukocytes. RESULTS: The baseline superoxide production of polymorphonuclear leukocytes was significantly increased by advanced glycation end-products in a dose-dependent manner. In contrast, in stimulated polymorphonuclear leukocytes advanced glycation end-products significantly inhibited superoxide production, again in a dose-dependent manner. This inhibitory effect of advanced glycation end-products was observed after dialyzing AGE-BSA, thereby eliminating the possible influence of reactive carbohydrates. No modification of superoxide production was seen with BSA and only a mild inhibitory effect of glucose at high concentrations. CONCLUSIONS: Advanced glycation end-products depress superoxide production by stimulated polymorphonuclear leukocytes. As superoxide plays an essential role in bactericidal activity, this polymorphonuclear leukocyte dysfunction may be a contributory factor to the increased prevalence and severity of bacterial infection seen in diabetic patients.

Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure.

A new exon 9 glucose-6-phosphate dehydrogenase mutation (G6PD "Rehovot") in a Jewish Ethiopian family with variable phenotypes.

Hereditary nonspherocytic hemolytic anemia (HNSHA) is a rare manifestation of glucose-6-phosphate dehydrogenase (G6PD) gene mutations, caused mainly by mutations located in exon 10 of the G6PD gene and less commonly by mutations in other parts of the gene. A new, exon 9, single-base mutation representing a T --> C transition at cDNA nucleotide 964 was found in three brothers and their carrier mother of Jewish Ethiopian descent. Biochemical characterization of the resultant protein was not performed. Though clinical manifestations included HNSHA in all cases, the severity of hemolysis and the transfusion requirement differed markedly. Severe congenital neutropenia (Kostmann's syndrome)--a disorder never reported before in conjunction with G6PD deficiency--was observed in one case. Levels of white blood cell G6PD activity of the three patients were 0-5% of normal controls. Neutrophil oxidative and bactericidal activities were inherently impaired in the patient with Kostmann's syndrome, but were well preserved in his two siblings.

Elevated salt and nitrate levels in drinking water cause an increase of blood pressure in schoolchildren.

AIM: To assess the influence on blood pressure in schoolchildren, of elevated sodium (Na(+)) and nitrate (NO(-)(3)) levels in the drinking water. METHODS: The blood pressure was recorded in three groups of age- and weight-matched schoolchildren (fourth and fifth graders) ingesting differing Na(+) and NO(-)(3) concentrations with their drinking water. Group 1 (n = 452) imbibed high-Na(+), high-NO(-)(3) water (196 and 49 mg/l, respectively); group 2 (n = 418) consumed low-Na(+), high-NO(-)(3) water (25 and 49 mg/l, respectively) and group 3 (n = 86) drank low-Na(+), low-NO(-)(3) water (35 and 25 mg/l, respectively). The chloride (Cl(-)) concentrations varied in parallel to those of Na(+). RESULTS: Systolic blood pressure (SBP) and mean arterial pressure (MAP) were significantly increased in group 1 versus groups 2 and 3 (115.6 +/- 12.2 and 86.4 +/- 9.6 mm Hg vs. 111.1 +/- 11.6 and 83 +/- 8.3 and 107 +/- 8.8 and 81 +/- 7.2 mm Hg, respectively, p < 0.05). The SBP in group 2 was also significantly higher than in group 3 (111.1 +/- 11.6 vs. 107 +/- 8.8 mm Hg; p < 0.05). CONCLUSIONS: Elevated Na(+) (and possibly Cl(-)) in combination with high NO(-)(3) concentrations in drinking water leads to an increase of SBP and MAP in fourth and fifth graders. The effects of Na(+) (and/or Cl(-)) and NO(-)(3) on SBP and MAP appear to be additive, yet independent of each other.

Paediatric Behçet disease manifested as recurrent myositis: from an incomplete to a full-blown form.

UNLABELLED: A 12-year-old boy presented with a limp and findings suggesting localised myositis of his right calf and a working diagnosis of Behçet disease was made. During 3 years of follow-up, he had another three episodes of calf myositis, all responsive to corticosteroids within days. CONCLUSION: A case of recurrent localised myositis as a main manifestation of Behçet disease is reported. The evolution of incomplete Behçet disease, which is common in children, to the full blown form, with the emphasis on muscle involvement and the importance of early diagnosis of Behçet disease, is discussed.